7. Project Summary/Abstract Over the past 35 years obesity rates have more than doubled in the United States, an outcome based largely on increased caloric consumption. The modern food environment is abundant with stimuli associated with rewarding food, and through learned associations these stimuli can override physiological satiation and satiety cues and trigger excessive food seeking and consumption. The hippocampus is a brain region traditionally linked with memory function and more recently with the higher-order learned control of both normal and excessive feeding behavior. Hippocampal neurons receive GI-derived satiation- and satiety-related signaling, in part, from the vagus nerve, as vagally-mediated satiation signals robustly activate hippocampal neurons. The role of GI-derived vagal signaling in regulating higher-order learned aspects of food intake control, however, is poorly understood. Furthermore, the structural connectivity mediating interactions between GI physiology and the hippocampus remains unexplored. Preliminary data in this proposal implicate a role of vagus nerve sensory signaling in hippocampal-dependent memory processes in rats. The principle goals of this proposal are to investigate the novel hypotheses that ablation of gastrointestinal (GI)-derived vagal sensory nerve disruption will negatively impact hippocampal-dependent learned control of appetitive behavior, accompanied by reductions in markers of neural plasticity and neurogenesis in hippocampal neurons (Aim 1). Additional experiments will utilize viral-based neuroanatomical methodologies to identify the multisynaptic/indirect pathways through which GI-derived vagal nerve signaling communicates to the hippocampus (Aim 2). To address these hypotheses, experiments in Aim 1 will utilize a novel and sophisticated surgical lesion of ~80% of GI-derived vagal afferent nerves, while leaving 100% of vagal motor signaling intact (CCK-saporin nodose ganglia injections) in combination with an array of rodent behavioral paradigms that examine hippocampal- dependent appetitive learning based on [1] interoceptive cues related to energy status, [2] external food reward-based contextual processing, and [3] social food-related cues. Aim 2 will utilize an innovative coinjection (COIN) neural tracing and dual viral tracing strategies to determine potential relay brain regions that connect vagal sensory signaling with hippocampal neurons. Collectively studies will identify behavioral, anatomical, and molecular mechanisms through which the vagus nerve influences cognition and feeding behavior.